tbuckley/cabot-search huggingface dataset:
Overall Survival and Exploratory Biomarker Analyses of Abemaciclib plus Trastuzumab with or without Fulvestrant versus Trastuzumab plus Chemotherapy in HR+, HER2+ Metastatic Breast Cancer Patients
Authors: Sara M. Tolaney, Shom Goel, Jorge Nadal, Hannelore Denys, Manuel R. Borrego, Lacey M. Litchfield, Jiangang Liu, Adams K. Appiah, Yanyun Chen, Fabrice André
Journal: Clinical Cancer Research (2023)

Abstract Purpose: The monarcHER trial has shown that abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, combined with fulvestrant and trastuzumab, improves progression-free survival (PFS) in hormone receptor–positive (HR+), HER2-positive (HER2+) advanced breast cancer (ABC) compared with standard-of-care (SOC) chemotherapy combined with trastuzumab. We report the final overall survival (OS) analysis, updated safety and efficacy data, and exploratory biomarker results from monarcHER. Patients and Methods: monarcHER (NCT02675231), a randomized, multicenter, open-label, phase II trial, enrolled 237 patients across Arm A (abemaciclib, trastuzumab, fulvestrant), Arm B (abemaciclib, trastuzumab), and Arm C (SOC chemotherapy, trastuzumab). Following the statistical plan, OS and PFS were estimated in all arms. RNA sequencing (RNA-seq) was performed on archival tissue. Results: Median OS was 31.1 months in Arm A, 29.2 months in Arm B, and 20.7 months in Arm C [A vs. C: HR, 0.71; 95% confidence interval (CI), 0.48–1.05; nominal two-sided P value 0.086; B vs. C: HR 0.83 (95% CI, 0.57–1.23); nominal two-sided P value 0.365]. Updated PFS and safety findings were consistent with previous results. The most frequently reported treatment-emergent adverse events included diarrhea, fatigue, nausea, neutrophil count decrease, and anemia. In exploratory RNA-seq analyses, Luminal subtypes were associated with longer PFS [8.6 vs. 5.4 months (HR, 0.54; 95% CI, 0.38–0.79)] and OS [31.7 vs. 19.7 months (HR, 0.68; 95% CI, 0.46–1.00)] compared with non-Luminal. Conclusions: In this phase II trial, abemaciclib + trastuzumab ± fulvestrant numerically improved median OS in women with HR+, HER2+ ABC compared with SOC chemotherapy + trastuzumab.
Human intestinal organoids from Cronkhite-Canada syndrome patients reveal link between serotonin and proliferation
Authors: Victoria Poplaski, Carolyn Bomidi, Amal Kambal, Hoa Nguyen-Phuc, Sara C Di Rienzi, Heather A Danhof, Xi-Lei Zeng, Linda A Feagins, Nan Deng, Eduardo Vilar, Florencia McAllister, Cristian Coarfa, Soyoun Min, Hyun Jung Kim, Richa Shukla, Robert Britton, Mary K Estes, Sarah E Blutt
Journal: Journal of Clinical Investigation (2023)

Cronkhite-Canada Syndrome (CCS) is a rare, noninherited polyposis syndrome affecting 1 in every million individuals. Despite over 50 years of CCS cases, the etiopathogenesis and optimal treatment for CCS remains unknown due to the rarity of the disease and lack of model systems. To better understand the etiology of CCS, we generated human intestinal organoids (HIOs) from intestinal stem cells isolated from 2 patients. We discovered that CCS HIOs are highly proliferative and have increased numbers of enteroendocrine cells producing serotonin (also known as 5-hydroxytryptamine or 5HT). These features were also confirmed in patient tissue biopsies. Recombinant 5HT increased proliferation of non-CCS donor HIOs and inhibition of 5HT production in the CCS HIOs resulted in decreased proliferation, suggesting a link between local epithelial 5HT production and control of epithelial stem cell proliferation. This link was confirmed in genetically engineered HIOs with an increased number of enteroendocrine cells. This work provides a new mechanism to explain the pathogenesis of CCS and illustrates the important contribution of HIO cultures to understanding disease etiology and in the identification of novel therapies. Our work demonstrates the principle of using organoids for personalized medicine and sheds light on how intestinal hormones can play a role in intestinal epithelial proliferation.
A PPARγ/long noncoding RNA axis regulates adipose thermoneutral remodeling in mice
Authors: Zhengyi Zhang, Ya Cui, Vivien Su, Dan Wang, Marcus J Tol, Lijing Cheng, Xiaohui Wu, Jason Kim, Prashant Rajbhandari, Sicheng Zhang, Wei Li, Peter Tontonoz, Claudio J Villanueva, Tamer Sallam
Journal: Journal of Clinical Investigation (2023)

Interplay between energy-storing white adipose cells and thermogenic beige adipocytes contributes to obesity and insulin resistance. Irrespective of specialized niche, adipocytes require the activity of the nuclear receptor PPARγ for proper function. Exposure to cold or adrenergic signaling enriches thermogenic cells though multiple pathways that act synergistically with PPARγ; however, the molecular mechanisms by which PPARγ licenses white adipose tissue to preferentially adopt a thermogenic or white adipose fate in response to dietary cues or thermoneutral conditions are not fully elucidated. Here, we show that a PPARγ/long noncoding RNA (lncRNA) axis integrates canonical and noncanonical thermogenesis to restrain white adipose tissue heat dissipation during thermoneutrality and diet-induced obesity. Pharmacologic inhibition or genetic deletion of the lncRNA Lexis enhances uncoupling protein 1-dependent (UCP1-dependent) and -independent thermogenesis. Adipose-specific deletion of Lexis counteracted diet-induced obesity, improved insulin sensitivity, and enhanced energy expenditure. Single-nuclei transcriptomics revealed that Lexis regulates a distinct population of thermogenic adipocytes. We systematically map Lexis motif preferences and show that it regulates the thermogenic program through the activity of the metabolic GWAS gene and WNT modulator TCF7L2. Collectively, our studies uncover a new mode of crosstalk between PPARγ and WNT that preserves white adipose tissue plasticity.
GLUT3 regulates alternative macrophage signaling through a glucose transport–independent role
Authors: Peng Zhang, Jason Miska, Amy B. Heimberger
Journal: Journal of Clinical Investigation (2023)

Macrophages are key mediators of innate immunity whose functional state can be regulated by glucose transporters. Although abundantly expressed in macrophages, the specific function of GLUT3, an isoform of facilitative glucose transporters, has not been clearly established. In this issue of the JCI, Dong-Min Yu and colleagues identify an alternative role for GLUT3 in promoting M2 macrophage polarization. The authors demonstrated that GLUT3 was upregulated upon M2 stimulation and was required for efficient alternative macrophage polarization and function. They further showed that GLUT3-induced M2 polarization was independent of glucose transport and functioned through Ras-mediated regulation of IL-4R endocytosis and IL-4/STAT6 activation. These findings may guide the development of macrophage-targeted treatments.
Inhibition of YTHDF1 by salvianolic acid overcomes gluten-induced intestinal inflammation
Authors: Ane Olazagoitia-Garmendia, Henar Rojas-Márquez, Maria del Mar Romero, Pamela Ruiz, Aloña Agirre-Lizaso, Yantao Chen, Maria Jesus Perugorria, Laura Herrero, Dolors Serra, Cheng Luo, Luis Bujanda, Chuan He, Ainara Castellanos-Rubio
Journal: Gut (2023)
Data quality and patient characteristics in European ANCA-associated vasculitis registries: data retrieval by federated querying
Authors: Karl Gisslander, Matthew Rutherford, Louis Aslett, Neil Basu, François Dradin, Lucy Hederman, Zdenka Hruskova, Hicham Kardaoui, Peter Lamprecht, Sabina Lichołai, Jacek Musial, Declan O’Sullivan, Xavier Puechal, Jennifer Scott, Mårten Segelmark, Richard Straka, Benjamin Terrier, Vladimir Tesar, Michelangelo Tesi, Augusto Vaglio, Dagmar Wandrei, Arthur White, Krzysztof Wójcik, Beyza Yaman, Mark A Little, Aladdin J Mohammad
Journal: Annals of the Rheumatic Diseases (2023)

Objectives This study aims to describe the data structure and harmonisation process, explore data quality and define characteristics, treatment, and outcomes of patients across six federated antineutrophil cytoplasmic antibody-associated vasculitis (AAV) registries. Methods Through creation of the vasculitis-specific Findable, Accessible, Interoperable, Reusable, VASCulitis ontology, we harmonised the registries and enabled semantic interoperability. We assessed data quality across the domains of uniqueness, consistency, completeness and correctness. Aggregated data were retrieved using the semantic query language SPARQL Protocol and Resource Description Framework Query Language (SPARQL) and outcome rates were assessed through random effects meta-analysis. Results A total of 5282 cases of AAV were identified. Uniqueness and data-type consistency were 100% across all assessed variables. Completeness and correctness varied from 49%–100% to 60%–100%, respectively. There were 2754 (52.1%) cases classified as granulomatosis with polyangiitis (GPA), 1580 (29.9%) as microscopic polyangiitis and 937 (17.7%) as eosinophilic GPA. The pattern of organ involvement included: lung in 3281 (65.1%), ear-nose-throat in 2860 (56.7%) and kidney in 2534 (50.2%). Intravenous cyclophosphamide was used as remission induction therapy in 982 (50.7%), rituximab in 505 (17.7%) and pulsed intravenous glucocorticoid use was highly variable (11%–91%). Overall mortality and incidence rates of end-stage kidney disease were 28.8 (95% CI 19.7 to 42.2) and 24.8 (95% CI 19.7 to 31.1) per 1000 patient-years, respectively. Conclusions In the largest reported AAV cohort-study, we federated patient registries using semantic web technologies and highlighted concerns about data quality. The comparison of patient characteristics, treatment and outcomes was hampered by heterogeneous recruitment settings.
Genomic insights into the mechanisms of FGFR1 dependency in squamous cell lung cancer
Authors: Netta Mäkinen, Matthew Meyerson
Journal: Journal of Clinical Investigation (2023)

Although subsets of patients with lung squamous cell carcinoma (LSCC) benefit from immunotherapy, there are few effective molecularly targeted treatments for LSCC. Fibroblast growth factor receptor (FGFR) inhibitors provide a therapeutic option for patients with LSCC harboring FGFR aberrations, but their therapeutic efficacy has been limited to date. In this issue of the JCI, Malchers et al. identified tail-to-tail rearrangements, either within or near FGFR1, that are associated with FGFR1 dependency and sensitivity to FGFR inhibition in LSCC. These results may help improve the selection of patients with LSCC who are most likely to benefit from treatment with FGFR inhibitors.
DUSP8 induces TGF-β–stimulated IL-9 transcription and Th9-mediated allergic inflammation by promoting nuclear export of Pur-α
Authors: Huai-Chia Chuang, Chia-Hsin Hsueh, Pu-Ming Hsu, Ching-Yi Tsai, Ying-Chun Shih, Hsien-Yi Chiu, Yi-Ming Chen, Wen-Kuang Yu, Ming-Han Chen, Tse-Hua Tan
Journal: Journal of Clinical Investigation (2023)

Dual-specificity phosphatase 8 (DUSP8) is a MAPK phosphatase that dephosphorylates and inactivates the kinase JNK. DUSP8 is highly expressed in T cells; however, the in vivo role of DUSP8 in T cells remains unclear. Using T cell-specific Dusp8 conditional KO (T-Dusp8 cKO) mice, mass spectrometry analysis, ChIP-Seq, and immune analysis, we found that DUSP8 interacted with Pur-α, stimulated interleukin-9 (IL-9) gene expression, and promoted Th9 differentiation. Mechanistically, DUSP8 dephosphorylated the transcriptional repressor Pur-α upon TGF-β signaling, leading to the nuclear export of Pur-α and subsequent IL-9 transcriptional activation. Furthermore, Il-9 mRNA levels were induced in Pur-α-deficient T cells. In addition, T-Dusp8-cKO mice displayed reduction of IL-9 and Th9-mediated immune responses in the allergic asthma model. Reduction of Il-9 mRNA levels in T cells and allergic responses of T-Dusp8-cKO mice was reversed by Pur-α knockout. Remarkably, DUSP8 protein levels and the DUSP8-Pur-α interaction were indeed increased in the cytoplasm of T cells from people with asthma and patients with atopic dermatitis. Collectively, DUSP8 induces TGF-β-stimulated IL-9 transcription and Th9-induced allergic responses by inhibiting the nuclear translocation of the transcriptional repressor Pur-α. DUSP8 may be a T-cell biomarker and therapeutic target for asthma and atopic dermatitis.
Bi-steric mTORC1 inhibitors induce apoptotic cell death in tumor models with hyperactivated mTORC1
Authors: Heng Du, Yu Chi Yang, Heng-Jia Liu, Min Yuan, John M Asara, Kwok-Kin Wong, Elizabeth P Henske, Mallika Singh, David J Kwiatkowski
Journal: Journal of Clinical Investigation (2023)

The PI3K/AKT/mTOR pathway is commonly dysregulated in cancer. Rapalogs exhibit modest clinical benefit, likely owing to their lack of effects on 4EBP1. We hypothesized that bi-steric mTORC1-selective inhibitors would have greater potential for clinical benefit than rapalogs in tumors with mTORC1 dysfunction. We assessed this hypothesis in tumor models with high mTORC1 activity both in vitro and in vivo. Bi-steric inhibitors had strong growth inhibition, eliminated phosphorylated 4EBP1, and induced more apoptosis than rapamycin or MLN0128. Multiomics analysis showed extensive effects of the bi-steric inhibitors in comparison with rapamycin. De novo purine synthesis was selectively inhibited by bi-sterics through reduction in JUN and its downstream target PRPS1 and appeared to be the cause of apoptosis. Hence, bi-steric mTORC1-selective inhibitors are a therapeutic strategy to treat tumors driven by mTORC1 hyperactivation.
Biomarkers of Pathologic Complete Response to Neoadjuvant Immunotherapy in Mismatch Repair–Deficient Colorectal Cancer
Authors: Jianxia Li, Huabin Hu, Ge Qin, Fan Bai, Xianrui Wu, Haoxian Ke, Jianwei Zhang, Yuqian Xie, Zehua Wu, Yang Fu, Hongbo Zheng, Longlong Gong, Zhi Xie, Yanhong Deng
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Immune checkpoint inhibitors (ICI) have become the standard of care for patients with mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) colorectal cancer. However, biomarkers of response to ICI are still lacking. Experimental Design: Forty-two patients with dMMR colorectal cancer treated with neoadjuvant PD-1 blockade were prospectively enrolled. To identify biomarkers of pathologic complete response (pCR) to neoadjuvant therapy, we analyzed genomic and transcriptomic profiles based on next-generation sequencing, and immune cell density based on multiplex immunofluorescence (mIF) staining. An integrated analysis of single-cell RNA sequencing from our previous study and GSE178341, as well as mIF was performed to further explore the significance of the tumor microenvironment (TME) on pCR response. Results: The tumor mutation burden of both tumor tissue and plasma blood samples was comparable between the pCR and non-pCR groups, while HLA-DQA1 and HLA-DQB1 were significantly overexpressed in the pCR group. Gene signature enrichment analysis showed that pathways including T-cell receptor pathway, antigen presentation pathway were significantly enriched in the pCR group. In addition, higher pre-existing CD8+ T-cell density was associated with pCR response (767.47 per.mm2 vs. 326.64 per.mm2, P = 0.013 Wilcoxon test). Further integrated analysis showed that CD8+ T cells with low PD-1 expression (PD-1lo CD8+ T cells) expressing high levels of TRGC2, CD160, and KLRB1 and low levels of proliferated and exhausted genes were significantly associated with pCR response. Conclusions: Immune-associated transcriptomic features, particularly CD8+ T cells were associated with pCR response to ICI in dMMR colorectal cancer. Heterogeneity of TME within dMMR colorectal cancer may help to discriminate patients with complete response to neoadjuvant ICI.
Author Correction: Blood–brain barrier injury and neuroinflammation induced by SARS-CoV-2 in a lung–brain microphysiological system
Authors: Peng Wang, Lin Jin, Min Zhang, Yunsong Wu, Zilei Duan, Yaqiong Guo, Chaoming Wang, Yingqi Guo, Wenwen Chen, Zhiyi Liao, Yaqing Wang, Ren Lai, Luke P. Lee, Jianhua Qin
Journal: Nature Biomedical Engineering (2023)
Cytosolic DNA accumulation promotes breast cancer immunogenicity via a STING-independent pathway
Authors: Jing Zhang, Hui Dai, Lei Huo, Jared K Burks, Daniel J McGrail, Shiaw-Yih Lin
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Immune checkpoint blockade (ICB) has revolutionized cancer treatment. However, ICB alone has demonstrated only benefit in a small subset of patients with breast cancer. Recent studies have shown that agents targeting DNA damage response improve the efficacy of ICB and promote cytosolic DNA accumulation. However, recent clinical trials have shown that these agents are associated with hematological toxicities. More effective therapeutic strategies are urgently needed. Methods Primary triple negative breast cancer tumors were stained for cytosolic single-stranded DNA (ssDNA) using multiplex immunohistochemical staining. To increase cytosolic ssDNA, we genetically silenced TREX1. The role of tumor cytosolic ssDNA in promoting tumor immunogenicity and antitumor immune response was evaluated using murine breast cancer models. Results We found the tumorous cytosolic ssDNA is associated with tumor-infiltrating lymphocyte in patients with triple negative breast cancer. TREX1 deficiency triggered a STING-independent innate immune response via DDX3X. Cytosolic ssDNA accumulation in tumors due to TREX1 deletion is sufficient to drastically improve the efficacy of ICB. We further identified a cytosolic ssDNA inducer CEP-701, which sensitized breast tumors to ICB without the toxicities associated with inhibiting DNA damage response. Conclusions This work demonstrated that cytosolic ssDNA accumulation promotes breast cancer immunogenicity and may be a novel therapeutic strategy to improve the efficacy of ICB with minimal toxicities.
Reply: How to define the futile outcome in patients undergoing surgery for perihilar cholangiocarcinoma
Authors: Francesca Ratti, Rebecca Marino, Bas Groot Koerkamp, Luca Aldrighetti
Journal: Hepatology (2023)

To the editor, We appreciate the thoughtful comments provided by Liu et al regarding our recent article. We agree with Liu et al about the importance of defining the period of severe postoperative complications. Recent developments in the hepatopancreatobiliary field have highlighted the significance of using a 90-day overall morbidity rate to assess surgical quality, especially for complex procedures like perihilar cholangiocarcinoma surgery. Aggressive resections inherently carry a higher risk of postoperative complications that may extend beyond the initial 30-day period. In our study, a 90-day postoperative period for severe postoperative complications was used, aligning with current best practices and quality measures. Readmissions, reinterventions, and complications are frequent throughout the entire first year after surgery for perihilar cholangiocarcinoma. Liu et al state that early recurrence (ER) within 1 year is a futile outcome. ER after surgical resection, however, may still offer the potential for survival beyond 1 year. Aggressive tumor biology and molecular factors can drive ER independently of the surgery itself. Furthermore, recent studies have demonstrated a notably improved prognosis where favorable infiltration patterns lead to improved disease-free and overall survival rates. Future developments in preoperative tumor molecular characterization have the potential to provide a better understanding of ER patterns, potentially opening new treatment avenues for a patient cohort that, as of today, has limited options beyond surgery.1 The ability to predict a "futile outcome" can help identify patients for whom the benefits of surgical resection are unequivocally diminished. The connection between ER and severe postoperative complications creates a detrimental cycle: complications delay adjuvant treatments, while complications worsen immunosuppression and inflammation, potentially leading to disease recurrence. Predicting this "futile outcome," through preoperative scoring, could help optimize management based on the patient's characteristics.2 Furthermore, even if patient death undoubtfully represents a failure of the surgical approach, it is not a sufficient reason to prevent a patient from undergoing surgery in cases of perihilar cholangiocarcinoma, where surgical resection is often the only potential chance for a cure.3 Each preoperative score predicting the risk of morbidity or mortality has a certain degree of accuracy, which means that potentially high-risk patients identified preoperatively may not actually experience a futile outcome. The aim of our scoring system is not to exclude patients from surgical intervention, but to identify those patients for whom preoperative optimization strategies are a feasible option, improving oncologic outcomes and reducing associated risks.
Metabolomic rewiring promotes endocrine therapy resistance in breast cancer
Authors: Songyeon Ahn, Jun Hyoung Park, Sandra L. Grimm, Danthasinghe Waduge Badrajee Piyarathna, Tagari Samanta, Vasanta Putluri, Dereck Mezquita, Suzanne A.W. Fuqua, Nagireddy Putluri, Cristian Coarfa, Benny Abraham Kaipparettu
Journal: Cancer Research (2023)

Approximately one-third of endocrine-treated women with estrogen receptor alpha-positive (ER+) breast cancers are at risk of recurrence due to intrinsic or acquired resistance. Thus, it is vital to understand the mechanisms underlying endocrine therapy resistance in ER+ breast cancer to improve patient treatment. Mitochondrial fatty acid β-oxidation (FAO) has been shown to be a major metabolic pathway in triple-negative breast cancer (TNBC) that can activate Src signaling. Here, we found metabolic reprogramming that increases FAO in ER+ breast cancer as a mechanism of resistance to endocrine therapy. A metabolically relevant, integrated gene signature was derived from transcriptomic, metabolomic, and lipidomic analyses in TNBC cells following inhibition of the FAO rate-limiting enzyme carnitine palmitoyl transferase 1 (CPT1), and this TNBC-derived signature was significantly associated with endocrine resistance in patients with ER+ breast cancer. Molecular, genetic, and metabolomic experiments identified activation of AMPK-FAO-oxidative phosphorylation (OXPHOS) signaling in endocrine-resistant ER+ breast cancer. CPT1 knockdown or treatment with FAO inhibitors in vitro and in vivo significantly enhanced the response of ER+ breast cancer cells to endocrine therapy. Consistent with the previous findings in TNBC, endocrine therapy-induced FAO activated the Src pathway in ER+ breast cancer. Src inhibitors suppressed the growth of endocrine-resistant tumors, and the efficacy could be further enhanced by metabolic priming with CPT1 inhibition. Collectively, this study developed and applied a TNBC-derived signature to reveal that metabolic reprogramming to FAO activates the Src pathway to drive endocrine resistance in ER+ breast cancer.